Human and Experimental Toxicology

Much confusion surrounds the concept of hormesis and what its biological meaning represents. This paper provides a definition of hormesis that addresses its historical foundations, quantitative features, and under-lying evolutionary and toxicologically based mechanistic strategies. Hormesis should be considered an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis. Given the limited magnitude of the stimulatory response (i.e., usually 30–60% greater than controls at maximum), heightened study design and replication requirements are often necessary to ensure reliable judgments on causality. Even though hormesis is considered an adaptive response, the issue of beneficial/harmful effects should not be part of the definition of hormesis, but reserved to a subsequent evaluation of the biological and ecological context of the response.

Identifying the ambient particulate matter (PM) fractions or constituents, critically involved in eliciting adverse health effects, is crucial to the implementation of more cost-efficient abatement strategies to improve air quality. This review focuses on the importance of different particle properties for PM-induced effects, and whether there is consistency in the results from epidemiological and experimental studies. An evident problem for such comparisons is that epidemiological and experimental data on the effects of specific components of ambient PM are limited. Despite this, some conclusions can be drawn. With respect to the importance of the PM size-fractions, experimental and epidemiological studies are somewhat conflicting, but there seems to be a certain consistency in that the coarse fraction (PM10-2.5) has an effect that should not be neglected. Better exposure characterization may improve the consistency between the results from experimental and epidemiological studies, in particular for ultrafine particles. Experimental data indicate that surface area is an important metric, but composition may play an even greater role in eliciting effects. The consistency between epidemiological and experimental findings for specific PM-components appears most convincing for metals, which seem to be important for the development of both pulmonary and cardiovascular disease. Metals may also be involved in PM-induced allergic sensitization, but the epidemiological evidence for this is scarce. Soluble organic compounds appear to be implicated in PM-induced allergy and cancer, but the data from epidemiological studies are insufficient for any conclusions. The present review suggests that there may be a need for improvements in research designs. In particular, there is a need for better exposure assessments in epidemiological investigations, whereas experimental data would benefit from an improved comparability of studies. Combined experimental and epidemiological investigations may also help answer some of the unresolved issues.

Arsenic (As) is one of the oldest poisons known to men. Its applications throughout history are wide and varied: murder, make-up, paint and even as a pesticide. Chronic As toxicity is a global environmental health problem, affecting millions of people in the USA and Germany to Bangladesh and Taiwan. Worldwide, As is released into the environment by smelting of various metals, combustion of fossil fuels, as herbicides and fungicides in agricultural products. The drinking water in many countries, which is tapped from natural geological resources, is also contaminated as a result of the high level of As in groundwater. The environmental fate of As is contamination of surface and groundwater with a contaminant level higher than 10 particle per billion (ppb) as set by World Health Organization (WHO). Arsenic exists in both organic and inorganic species and either form can also exist in a trivalent or pentavalent oxidation state. Long-term health effects of exposure to these As metabolites are severe and highly variable: skin and lung cancer, neurological effects, hypertension and cardiovascular diseases. Neurological effects of As may develop within a few hours after ingestion, but usually are seen in 2—8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain—Barré syndrome. The predominant clinical features of neuropathy are paresthesias, numbness and pain, particularly in the soles of the feet. Electrophysiological studies performed on patients with As neuropathy have revealed a reduced nerve conduction velocity, typical of those seen in axonal degeneration. Most of the adverse effects of As, are caused by inactivated enzymes in the cellular energy pathway, whereby As reacts with the thiol groups of proteins and enzymes and inhibits their catalytic activity. Furthermore, As-induced neurotoxicity, like many other neurodegenerative diseases, causes changes in cytoskeletal protein composition and hyperphosphorylation. These changes may lead to disorganization of the cytoskeletal framework, which is a potential mechanism of As-induced neurotoxicity. Human & Experimental Toxicology (2007) 26, 823— 832

Blooms of cyanobacteria or blue-green algae are known to have caused poisoning in fish, waterfowl, animals and man. One of the toxins responsible for this is the hepatotoxin microcystin-LR which has been found to occur in blooms present intermittently in sources used for domestic water supplies. Three sets of experiments were undertaken to investigate the acute toxicity of microcystin-LR in mice and rats by the oral and intraperitoneal routes, the potential for effects on foetal development in the mouse, and the effects of repeated oral dosing over 13 weeks in the mouse. The results of this work were as follows: (1) Microcystin-LR is 30-100 times less toxic via oral ingestion than via intraperitoneal injection; (2) Microcystin-LR is not a selective developmental toxicant in the mouse. There was a No Observed Adverse Effect Level (NOAEL) of 600 μg kg^-1 bodyweight per day given on days 6-15 of pregnancy for any form of developmental toxicity; (3) There was a clear NOAEL for tissue damage in the liver of 40 μg kg^-1 bodyweight per day of microcystin-LR. Using this data, a value of 1 μg l^-1 microcystin-LR would be an appropriate guideline value for drinking water.

The concern of a terrorist attack using cyanide, as well as the gradual awareness of cyanide poisoning in fire victims, has resulted in a renewed interest in the diagnosis and treatment of cyanide poisoning. The formerly academic presentation of cyanide poisoning must be replaced by more useful knowledge, which will allow emergency physicians and rescue workers to strongly suspect cyanide poisoning at the scene. Human cyanide poisonings may result from exposure to cyanide, its salts, or cyanogenic compounds, while residential fires are the most common condition of exposure. In fire victims, recognition of the cyanide toxidrome has been hampered by the short half-life in blood and poor stability of cyanide. In contrast, carboxyhemoglobin, as a marker of carbon monoxide poisoning, is easily measured and long-lasting. No evidence supports the assumption of the arbitrary fixed lethal thresholds of 50% for carboxyhemoglobin, and 3 mg/L for cyanide, in fire victims. Preliminary data, drawn when comparing pure carbon monoxide and pure cyanide poisonings, suggest that a cyanide toxidrome can be defined considering signs and symptoms induced by cyanide and carbon monoxide, respectively. Prospective studies in fire victims may provide value in clarifying signs and symptoms related to both toxicants. Cyanide can induce a lifethreatening poisoning from which a full recovery is possible. A number of experimentally efficient antidotes to cyanide exist, whose clinical use has been hampered due to serious side effects. The availability of potentially safer antidotes unveils the possibility of their value as first-line treatment, even in a complex clinical situation, where diagnosis is rapid and presumptive.

Methanol, a potent toxicant in humans, occurs naturally at a low level in most alcoholic beverages without causing harm. However, illicit drinks made from “industrial methylated spirits” [5% (v/v) methanol:95% (v/v) ethanol] can cause severe and even fatal illness. Since documentation of a no-adverse-effect level for methanol is nonexistent in the literature a key question, from the public health perspective, is what is the maximum concentration of methanol in an alcoholic drink that an adult human could consume without risking toxicity due to its methanol content? Published information about methanol-intoxicated patients is reviewed and combined with findings in studies in volunteers given small doses of methanol, as well as occupational exposure limits (OELs), to indicate a tolerable (“safe”) daily dose of methanol in an adult as 2 g and a toxic dose as 8 g. The simultaneous ingestion of ethanol has no appreciable effect on the proposed “safe” and “toxic” doses when considering exposure over several hours. Thus, assuming that an adult consumes 425-ml standard measures of a drink containing 40% alcohol by volume over a period of 2 h, the maximum tolerable concentration (MTC) of methanol in such a drink would be 2% (v/v) by volume. However, this value only allows a safety factor of 4 to cover variation in the volume consumed and for the effects of malnutrition (i.e., folate deficiency), ill health and other personal factors (i.e., ethnicity). In contrast, the current EU general limit for naturally occurring methanol of 10 g methanol/l ethanol [which equates to 0.4% (v/v) methanol at 40% alcohol] provides a greater margin of safety.

1 In vitro studies with human erythrocyte acetylcholin esterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning.

2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazi non and other OPs is characterized by slow sponta neous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly sus ceptible to reactivation by oximes.

3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HLö 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent.

4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 μg/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re-inhibition of reactivated AChE in the first days following intoxication.

5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.

1 The toxicokinetics of paraquat were studied in 18 cases of acute human poisoning using a specific radioimmunoassay. Plasma paraquat concentration exhibited a mean distribution half-life ( t_½ α) of 5 h and a mean elimination half-life ( t_½ β) of 84 h. Cardiovascular collapse supervened early during the course of the intoxication and was associated with the distribution phase. Death related to pulmonary fibrosis occurred late and was associated with the elimination phase.

2 Pharmacokinetic analysis of urine paraquat excretion confirmed the biphasic decline of paraquat. Moreover, renal paraquat and creatinine clearances were not correlated but renal paraquat clearance was never higher than the renal creatinine clearance.

3 Tissue paraquat distribution was ubiquitous with an apparent volume of distribution ranging from 1.2 to 1.6 l/kg. Muscle could represent an important reservoir explaining the long persistence of paraquat in plasma and urine for several weeks or months after poisoning.

Terminalia chebula Gertn. (Combetraceae) is an important herbal drug in Ayurvedic pharmacopea. In the present study, a 95% ethanolic extract of T. chebula (fruit) (TC extract), which was chemically characterized on the basis of chebuloside II as a marker, was investigated for hepatoprotective activity against anti-tuberculosis (anti-TB) drug-induced toxicity. TC extract was found to prevent the hepatotoxicity caused by the administration of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) (in combination) in a sub-chronic mode (12 weeks). The hepatoprotective effect of TC extract could be attributed to its prominent anti-oxidative and membrane stabilizing activities. The changes in biochemical observations were supported by histological profile.

Polychlorinated biphenyls (PCBs) and dioxins are potentially toxic compounds which occur widely in the environment. Their effects on the growth and development of infants at the levels currently found in highly industrialised western countries is not well known. This Dutch multicenter study, combining animal and human studies, tries to answer this question.

Animal studies showed that PCB 169, given once during pregnancy at a dose of 1.8 g kg^-1 bodyweight, has an effect on developmental parameters, dopamine regulation and fertility. Effects on thyroid hormones were also found in animals, probably due to both a competitive binding of PCB metabolites to the thyroxine binding protein and increased glucuronidation, Perhaps to compensate for this, an increased diodase activity in the brain was found. Human studies involved 400 mother-infant pairs, half of them being breast-fed, the other half were fed a formula devoid of PCBs and dioxins. PCB levels were measured in serum and dioxin and PCB levels in breastmilk. Levels were found to be as high as previously found in highly industrialised countries. Growth and development were carefully documented, but no data are as yet available. In pregnant women, a significant negative correlation was found between some dioxin and PCB congeners in milk and plasma thyroid hormones, while newborn infants showed higher thyroid stimulating hormone (TSH) at higher levels of dioxin exposure.

In summary, data from this combined multicenter study involving animals and humans increases our insight into the potentially negative effects of PCBs and dioxins on growth and development.